Tectonic gene mutations in patients with Joubert syndrome

Abstract

So far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS) in patients with Joubert syndrome, we identified two more patients and summarize what is currently known about the phenotypes associated with sequence variants in these genes. In a boy aged 12 years with intellectual disability and the classical molar tooth sign on MRI, a homozygous splice-site sequence variant in TCTN3 leading to in-frame skipping of exon 7 was detected. A previously described non-truncating sequence variant in TCTN3 was also associated with Joubert syndrome, whereas four truncating sequence variants were detected in patients with MeckelGruber or Mohr-Majewski syndrome. The second patient, a boy aged 7 years with severe psychomotor retardation, was found to carry a homozygous canonic splice-site sequence variant in TCTN2. So far, only three sequence variants associated with Joubert syndrome and two with Meckel-Gruber syndrome have been described in this gene. Reviewing the clinical data on patients with sequence variants in the tectonic genes TCTN1-3 reveals that all of them have a neurological phenotype with vermis hypoplasia or occipital encephalocele associated with severe intellectual disability in the surviving patients. In contrast, other features frequently seen in patients with ciliopathies such as nephronophthisis, liver fibrosis, retinal dystrophy or coloboma have not been reported. Our patients emphasize the usefulness and efficacy of a comprehensive NGS panel approach. A concise genetic diagnosis may help to prevent unnecessary investigations and improve the clinical management of these patients.

Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition

“…Of these, all except RPGRIP1L, NPHP3, and KIF14 encode identified components of the MKS complex (Chih et al 2011; Dowdle et al 2011; Garcia-Gonzalo et al 2011; Sang et al 2011; Roberson et al 2015; Lambacher et al 2016). Some of these genes (i.e., TMEM216, TMEM67, CEP290, RPGRIP1L, CC2D2A, TCTN2, TCTN3, and TMEM231) are also mutated in a milder ciliopathy, Joubert syndrome (JBTS), defined by a specific cerebellar malformation, the molar tooth sign, but usually also including polydactyly (Valente et al 2014; Huppke et al 2015). The differences in phenotype and severity of these two recessive Mendelian syndromes suggest that MKS results from homozygous null mutations in these genes, whereas JBTS results from the involvement of at least one hypomorphic allele (Delous et al 2007; Mougou-Zerelli et al 2009; Iannicelli et al 2010).…”

Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

“…Therefore, Joubert syndrome has a high degree of overlapping clinical features with many other ciliopathies including Meckel-Gruber syndrome, which suggests their molecular basis involved in the pathogenesis of ciliopathies may have some congruity in some ways. Compared with Joubert syndrome by other genes, frequent symptoms such as nephronophthisis, liver fibrosis, retinal dystrophy or coloboma have not been reported in patients caused by tectonic gene mutations; however, intellectual disability is more often observed in tectonic gene mutation-caused Joubert syndrome [28]. In tectonic genecausative Joubert syndrome, the defects of TCTN2 and TCTN3 lead to more severe symptoms than the defects of TCTN1 in patients with Joubert syndrome [28].…”

“…A compound heterozygous TCTN2 mutation (c.1117G>A [p.G373R] and c.76delG[p. D26TfsX26] ) contributed to Joubert syndrome in a Caucasian male child who died at 13 months [27]. A homozygous TCTN2 mutation (c.1235-1G>A) was identified in a male patient with postaxial hexadactyly, hypotonia, nystagmus, hyperopia, ataxic gait and typical MTS on MRI [28]. Similarly, TCTN3 mutations are also the causes of Joubert syndrome.…”

“…TCTN1, TCTN2, and TCTN3 proteins interact with each other and with other proteins involved in the pathogenesis of Meckel-Gruber syndrome like Tmem216, Tmem67, Cep290, and B9d1 in the transition zone between the basal body and the ciliary axoneme of primary cilia [28]. Therefore, Joubert syndrome has a high degree of overlapping clinical features with many other ciliopathies including Meckel-Gruber syndrome, which suggests their molecular basis involved in the pathogenesis of ciliopathies may have some congruity in some ways.…”

The Hedgehog pathway: role in cell differentiation, polarity and proliferation

“…Tectonic 1/2, on the other hand, is involved in ciliary transportation of membrane-associated proteins, such as SMO (Garcia-Gonzalo et al 2011). Mutations of tectonic1/2 genes have been found in several genetic disorders such as Meckel and Joubert syndromes (Garcia-Gonzalo et al 2011; Huppke et al 2014; Shaheen et al 2011). …”